Letter
作者: Ehrlich, Lauren I R ; Ford, Kyle ; Dekker, Joseph D ; Zhang, Xiaoyan M ; Triplett, Todd A ; Schreiber, Taylor H ; Yamany, Mena S ; Blazeck, John ; Donkor, Moses ; Stone, Everett ; Sentandreu, Enrique ; Kumada, Yoichi ; Marshall, Nicholas ; Fromm, George ; Lamb, Candice ; Lu, Wei-Cheng ; Manfredi, Mark ; Tanno, Yuri ; Tan, Bing ; Qerqez, Ahlam ; Tiziani, Stefano ; Garrison, Kendra C ; Georgiou, George ; McGovern, Karen ; Coma, Silvia ; Karamitros, Christos S
Increased tryptophan (Trp) catabolism in the tumor microenvironment (TME) can mediate immune suppression by upregulation of interferon (IFN)-γ-inducible indoleamine 2,3-dioxygenase (IDO1) and/or ectopic expression of the predominantly liver-restricted enzyme tryptophan 2,3-dioxygenase (TDO). Whether these effects are due to Trp depletion in the TME or mediated by the accumulation of the IDO1 and/or TDO (hereafter referred to as IDO1/TDO) product kynurenine (Kyn) remains controversial. Here we show that administration of a pharmacologically optimized enzyme (PEGylated kynureninase; hereafter referred to as PEG-KYNase) that degrades Kyn into immunologically inert, nontoxic and readily cleared metabolites inhibits tumor growth. Enzyme treatment was associated with a marked increase in the tumor infiltration and proliferation of polyfunctional CD8+ lymphocytes. We show that PEG-KYNase administration had substantial therapeutic effects when combined with approved checkpoint inhibitors or with a cancer vaccine for the treatment of large B16-F10 melanoma, 4T1 breast carcinoma or CT26 colon carcinoma tumors. PEG-KYNase mediated prolonged depletion of Kyn in the TME and reversed the modulatory effects of IDO1/TDO upregulation in the TME.
默克制药（江苏）有限公司初创企业
